A Role for Tumor Necrosis Factor Receptor-2 and Receptor-interacting Protein in Programmed Necrosis and Antiviral Responses

Chan, Francis Ka Ming; Shisler, Joanna L.; Bixby, Jacqueline G.; Felices, Martin; Zheng, Lixin; Appel, Michael C.; Orenstein, Jan; Moss, Bernard; Lenardo, Michael J.

doi:10.1074/jbc.m305633200

Cited by 418 publications

(398 citation statements)

References 33 publications

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“…S1B), suggesting that cells are not committed to apoptosis. Apoptosis commonly suppresses programmed necrosis via active caspase-8, which is able to cleave RIP1 (33,34), CYLD (35), and RIP3 (36). In many situations, programmed necrosis proceeds only when caspase-8 activation is compromised by chemical or viral inhibitors (3).…”

Section: Discussionmentioning

confidence: 99%

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Wang

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

196

193

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The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domaincontaining adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.programmed necrosis | HSV-1 | ICP6 | RIP3 | MLKL C ell death triggered by pathogens is a crucial component of mammalian host-defense system. Apoptosis, a predominant programmed cell death in mammals, functions as an effective host-defense mechanism for preventing pathogen replication. Apoptosis is initiated by either mitochondria or cell-death receptors, and it is executed by a group of cysteine proteases called caspases (1). The apoptotic pathway can be subverted by pathogen-encoded apoptotic suppressors such as caspase inhibitors (2). Recent studies have revealed that caspase inhibition can lead to alternative activation of necrosis, releasing the damage-associated molecular patterns (DAMPs) signal to trigger the activation of the host immune system (3, 4).Cytokines of the TNF family are classical inducers of programmed necrosis that are morphologically characterized by the swelling of intracellular organelles and disrupted plasma membranes. Programmed necrosis triggered by death cytokines such as TNF, also known as necroptosis (5-7), is tightly regulated by receptor-interacting kinase-1 (RIP1) (8), its deubiquitin enzyme cylindromatosis (CYLD) (9), and receptor-interacting kinase-3 (RIP3) (10-12). The RIP homotypic interaction motif (RHIM) domains of RIP1 and RIP3 are required for the formation of the RIP1-RIP3 complex that is called a necrosome (13). Recently, mixed lineage kinase domain-like (MLKL) protein has been identified as a functional substrate of RIP3 kinase (14, 15). Upon phosphorylation, ...

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Section: Discussionmentioning

confidence: 99%

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Wang

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

196

193

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“…Others suggest a socalled ''ligand-passing'' mechanism by which TNFR2 binds TNF and allows an increased concentration of TNF to be passed on to TNFR1 to activate the apoptotic machinery [14]. Finally, some authors support the concept that stimulation of TNFR2 potently enhances TNFR1-transduced cell death via a more direct effect of TNFR2 on cell viability [40][41][42]. Our results obtained from the co-transfer of WT and TNFR2 À/À CD4 + T cells clearly demonstrate that the differential susceptibility to AICD is a direct effect of the TNFR2 expression by the CD4 + T cells and is not caused by a TNFR2-induced secretion of secondary mediators, which then mediate the increased susceptibility to AICD.…”

Section: Discussionmentioning

confidence: 99%

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

et al. 2009

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TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4 + T-cell transfer model of colitis using TNFR2 À/À or WT mice as donors of colitogenic CD4 + CD45RB hi T cells for transfer into syngeneic RAG2 À/À or RAG2 À/À TNFR2 À/À recipient mice. Although the absence of TNFR2 expression by nonlymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2 À/À CD4 + T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2 À/À CD4 1 T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2 À/À CD4 1 T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders.Key words: CD4 1 T cells Á Inflammation Á Intestinal immunity Á TNF Introduction TNF plays a fundamental role in immunity and inflammation based on its pleiotropic effects on differentiation, growth and apoptotic cell death of both immune and non-immune cell subsets [1,2]. It is well established that TNF is also critically involved in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, MS and inflammatory bowel diseases (IBD) [3]. Monocytes and macrophages are the main producers of TNF, but T and B lymphocytes and also mast cells can produce significant amounts of TNF. Interestingly, intestinal cell lines are induced to synthesize TNF upon infection with invasive bacterial strains [4]. TNF mediates its functions by binding as a trimer to either TNF receptor (TNFR) 1 or 2. The binding of TNF trimer to the preassembled TNFR complex leads to conformational changes of the receptors facilitating signal transduction through rapid recruitment of downstream signaling molecules. Both receptors have distinct signal transduction pathways and mediate distinct cellular responses [1,[5][6][7][8][9][10]. The 55 kDa receptor, TNFR1 (also known as p55, p60, TNFRSF1a, CD120a) is expressed on most cell types. The intracellular domain of TNFR1 contains a death domain (DD) that leads to apoptosis through caspase activation. TNFR1 signaling can also mediate transcription of anti-apoptotic proteins, inflammatory cytokines and chemokines through activation of NF-kB. The 75 kDa receptor, TNFR2 (also known as p75, p80, TNFRSF1b, CD120b), is Eur. J. Immunol. 2009. 39: 1743-1753 DOI 10.1002 Cellular immune response 1743 expressed predominantly by haematopoietic cells, but expression by other cell types can be i...

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“…Examination of cells from TNF-␣ receptor-deficient mice suggested that both TNFRI and TNFRII were involved together in the optimal suppressive effect. In most circumstances, TNFRI appears to the predominant activating receptor for TNF-␣, but a number of situations have been reported in which TNFRII can participate as a potential partner in cell stimulation (36,37). Both TNFRI and TNFRII have been shown to be involved in cPLA 2 activation.…”

Section: Discussionmentioning

confidence: 99%

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

McPhillips

Janssen

Ghosh

et al. 2007

The Journal of Immunology

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Removal of apoptotic cells from inflammatory sites is an important step in the resolution of inflammation. Both murine and human macrophages stimulated with TNF-α or directly administered arachidonic acid showed an impaired ability to ingest apoptotic cells (efferocytosis). The inhibition was shown to be due to generation of reactive oxygen species, was blocked with a superoxide dismutase mimetic, MnTBAP, and was mimicked by direct addition of H2O2. To determine the mechanism of TNF-α-stimulated oxidant production, bone marrow-derived macrophages from gp91phox-deficient mice were examined but shown to still produce oxidants and exhibit defective apoptotic cell uptake. In contrast, a specific cytosolic phospholipase A2 inhibitor blocked the oxidant production and reversed the inhibited uptake. The suppressive effect of endogenous or exogenous oxidants on efferocytosis was mediated through activation of the GTPase, Rho. It was reversed in macrophages pretreated with C3 transferase to inactivate Rho or with an inhibitor of Rho kinase. During maturation of human monocyte-derived macrophages, only mature cells exhibited TNF-α-induced suppression of apoptotic cell clearance. The resistance of immature macrophages to such inhibition was shown to result not from defective generation of oxidants, but rather, from lack of response of these cells to the oxidants. Overall, the data suggest that macrophages in a TNF-α- and oxidant-rich inflammatory environment are less able to remove apoptotic cells and, thereby, may contribute to the local intensity of the inflammatory response.

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A Role for Tumor Necrosis Factor Receptor-2 and Receptor-interacting Protein in Programmed Necrosis and Antiviral Responses

Cited by 418 publications

References 33 publications

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

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A Role for Tumor Necrosis Factor Receptor-2 and Receptor-interacting Protein in Programmed Necrosis and Antiviral Responses

Cited by 418 publications

References 33 publications

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

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Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis